Voltage activated KCNQ potassium (“K+”) channels, provide the molecular basis for slowly activating delayed-rectifier K+ (IKs) current in the heart, M-currents in neurons which regulate the firing rate of neurons in the central nervous system and potassium currents in cochlear hair cells. IKs is composed of an α subunit, KCNQ1, and a β subunit, KCNE1 (also known as minK) (see Sanguinetti, M C. et al., Nature (1996) 384: 80-83.), while heteromultimers of KCNQ2, KCNQ3 and KCNQ5 subunits form the basis for the M-channel and KCNQ4 channels form K+ currents of the cochlear outer hair cells and vestibular utricle in the inner ear. Mutations within the KCNQ channel proteins, KCNQ1-5 (otherwise known as Kv7.1-5 or KvLQT1-5) are associated with cardiac arrhythmias (see Wang, Q. et al., Nat. Genetics (1996)12:17-23; Tester, D J. et al., Heart Rhythm. (2005) 2: 507-517), epilepsy (see Brown, D A., J. Physiology (2008) 586: 1781-1783; Singh, N A. et al., Nat. Genetics (1998) 18:25-29) and deafness (see Brown D A. (2008)).
The crystal structures of several voltage-gated potassium channels have been elucidated and extensively studied (see Jiang, Y. et al., Nature (2003) 423:33-41; Long S B. et al Science. (2005) 309: 897-908), however structural modeling of KCNQ channels is incomplete. Although KCNQ channels are structurally similar to other voltage-gated K+ channels, the crystal structure has not yet been solved leading to conflicting results in the literature regarding the characterization of essential PIP2 and ATP binding domains as well as the voltage dependant activation motifs. See Thomas, A M. et al., J. Biol. Chem. (2011) 286(3):2088-100; Hernandez, C C. et al., J. Gen. Physiol. (2008) 132: 361-381).